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A patient with classical Kaposi's sarcoma and angiosarcoma: Bad luck or a common aetiology?
Clinical Oncology (1997) 9:186-188 © 1997 The Royal College of Radiologists
Clinical Oncology
Case Report A Patient with Classical Kaposi's Sarcoma and Angiosarcoma: Bad Luck or a Common Aetiology? M. C. Steiner ~, M. E. F. Smith 2, M. F.Spittle 1 IThe Middlesex Hospital, 2UCL Medical School, London, UK
Abstract. Classical Kaposi's sarcoma and angiosarcoma are rare malignant turnouts arising from vascular tissue. However, they have distinct histological features and appear also to differ in their epidemiology and pathogenesis. We present the case history of a patient in whom both these turnouts occurred simultaneously. The relationship between these events is discussed in the light of the new viris, human herpes virus 8.
Keywords: Angiosarcoma; Human herpesvirus 8; Kaposi's Sarcoma
intermittendy required radiotherapy to the right foot and left hand. He did not develop significant limb lymphoedema. In April 1994 he presented again, with a lump behind the right knee, which had appeared 4 months previously. This region had not been irradiated previously. Clinical examination revealed a 4 cm red mass in the right popliteal fossa (Fig. 3). The lesion was biopsied and the histology showed a malignant vasoformative tumour with the features of angiosarcoma. The tumour comprised irregular anastomosing vessels lined by very plump and atypical endothelial cells (Fig. 4), with occasional tufting and a solid cell component, which was partly spindled and
CASE REPORT A 60-year-old, married man presented in 1983 with an 8year history of purple lesions on the feet. More recently, these had also appeared on the hands. He was of Catholic Sicilian origin, although he had lived in the UK for 30 years. His medical history included syncopal episodes and atrial fibrillation. At the time of presentation, his medications were phenytoin 300 mg at night and digoxin 0.125 mg daily. There was no family history of note. On examination, there were lesions typical of Kaposi's sarcoma (KS) on the feet and hands (Fig. 1). A biopsy specimen was taken from a lesion on his foot. The histology showed complex, irregularly shaped, dilated vascular channels in the dermis, lined by endothelial cells, some of which were atypical. The abnormal vessels were closely related to groups of plasma cells associated with abundant haemosiderin. No spindle cell component was seen. These features (Fig. 2) are diagnostic of Kaposi's sarcoma (patch phase). Immunological studies were performed, which demonstrated a defect in monocyte function. Precise details of these studies were unfortunately not available. The lymphocyte count and the helper/suppressor cell count ratio were normal. The patient's left foot was treated with a single fraction of 8 Gy midline dose radiation, using a cobalt-60 machine with lateral opposed fields. Six months later, the right foot required treatment and he received 15 Gy midline dose in five fractions with megavoltage photons. Over the next few years the condition remained indolent, although the patient
and offprint requests to. Dr M. Spittle, Department of Clinical Oncology, The Middlesex Hospital, Mortimer Street, London W1N 8AA, UK. Correspondence
Fig. 1. Typical lesions of Kaposi's sarcoma.
Fig. 2. Histological diagnostic features of Kaposi's sarcoma (patch phase).
187
A Patient with Classical Kaposi's Sarcoma and Angiosarcoma DISCUSSION
Fig. 3. Mass (4 cm) in the right popliteal fossa.
Fig. 4. Histological appearance of the mass shown in Fig. 3 showing the features of angiosarcoma.
partly epithelioid. Immunohistochemistry demonstrated that the turnout cells expressed CD3I, but lacked Factor VIII-related antigen. CD31 expression is highly specific for endothelial differentiation in the context of mesenchymal cells [1]. In view of this diagnosis and the site of disease, a wide local excision was performed followed by skin grafting. In April 1995, new lesions appeared on the dorsum and sole of the right foot, which were atypical of KS. These arose in areas of skin that had not been irradiated. The histology of a biopsy from the sole of the foot showed angiosarcoma, the appearances being similar to those of the previous biopsy from the popliteal fossa.
Classic (non HIV-related) KS is a rare tumour occurring in elderly males of Jewish or Mediterranean origin. Although it typically runs an indolent course, studies of the natural history of the disease have demonstrated an increase in the incidence of second malignancy in these patients, particularly involving the lymphoreticular system. Two such studies reported the rates of second malignancy to be 37% [2] and 15% [3] respectively. To our knowledge, the association of classic KS and angiosarcoma has not been reported. The geographical and racial distribution of classic KS suggests a genetic or environmental agent as a cause for the disease; this hypothesis has been supported by the discovery of herpesvirus-like DNA sequences from the virus termed human herpesvirus 8 (HHV8) in samples of tissue from patients with both AIDS-related and classic KS [4-6]. The occurrence of the disease in individuals with HIV infection, and in those receiving immunosuppressive therapy following organ transplantation, indicates that host defence factors are also crucial in the pathogenesis of this condition. Weltfriend et al. studied immune function in a group of patients with classic KS and found normal T4fr8 ratios, but significantly impaired natural killer cell function when compared with healthy controls [7]. It is likely that impaired immune function is not only a factor in the pathogenesis of classic KS but is also related to the high rate of lymphoproliferative malignancy found in these patients. Immunological studies in our patient showed an abnormality of monocyte function, the precise records of which were not available. We are therefore unable to ascertain whether this defect was implicated in the pathogeneis of this condition in this patient. Angiosarcoma is a clinically aggressive, malignant tumour showing endothelial differentiation. Holden et al. studied 72 patients who developed angiosarcoma on the head and neck (where it classically appears) and reported a 12% survival at 5 years [8]. This tumour has been widely reported in association with lymphoedema and prior irradiation [9]. Recently, HHV8 DNA sequences have been found both in angiolymphoid hyperplasia, eosinophilia and angiosarcoma [6]. Thus it is likely that the coexistence of these two malignancies in one patient can be attributed to the involvement of HHV8. The HHV8 status of this patient was not determined, but can be considered positive, as it is in almost all cases of KS. Although both KS and angiosarcoma show endothelial differentiation, their histological appearance are distinct [1]. The angiosarcoma in this patient appeared in a region that had not been previously irradiated, excluding this as an aetiological factor. Similarly, there was no lymphoedema at the site of the tumour. Since KS and angiosarcoma are both endothelial malignancies, it is perhaps surprising that angiosarcoma does not more often develop from preexisting KS lesions. This does not imply either distinct forms of endothelial differentiation in the two tumour types or little overlap in the genetic mutations that underlie their development. Although angiosarcoma does not appear to be associated with immunosuppression, Chadwick et al. have reported the occurrence of other soft tissue sarcomas (leiomysarcomas and leiomyomas) in children infected with HIV [10]. in addition, the Epstein-Barr virus (EBV) has been found in sarcomatous tissue taken from these children, but not in sarcomas from non-HIV controls [11]. The authors suggest that EBV infection in immunocompromised individuals may contribute to the pathogenesis of sarcomas. It is of interest that EBV has also been implicated in the pathogenesis of body cavity-based B-cell lymphomas in HIV-infected individuals, often in association with the
188 presence of KS-related herpesvirus [12]. These findings led support to the hypothesis that viral infection is an important factor in the development of tumours in the immunosuppressed. Such viruses are also likely to play a role in the pathogenesis of classic KS and may be involved in the development of multiple primary malignancies in these patients.
SUMMARY The circumstances underlying the occurrence of multiple primary malignancies in patients with classic KS has yet to be established. Both angiosarcoma and classic KS are derived from endothelial tissue, but the factors underlying their development appear to be distinct. Although it is likely that a combination of environmental and immunological factors resulted in the occurrence of these tumours in this patient, the relevant feature is the implication of HHV8 in both of these and other endothelial cell-derived malignancies [13]. This is the first reported occurrence of the coexistence of these two tumours.
References 1. Enzinger FM, Weiss SW. Malignant vascular tumours. In: Soft tissue tumours, third edition. St Louis, MO: C. V. Mosby, 641-77.
M.C. Steiner et al. 2. Safai B, Mike V, Giraldo G, et al. Association of Kaposi's sarcoma with second primary malignancies. Possible etiopathogenic implications. Cancer 1980;45:1472-9. 3. Friedman-Birnbaum R, Weltfriend S, Katz I. Kaposi's sarcoma: retrospective study of 67 cases with the classical form. Dermatologica 1990;180:13-17. 4. Huang YQ, Li JJ, Kaplan MH, et al. Herpes virus-like nucleic acid in various forms of Kaposi's sarcoma. Lancet 1995; 345:759-61. 5. Dupin N, Grandadam M, Calvez V, et al. Herpes virus-like DNA sequences in patients with Mediterranean Kaposi's sarcoma. Lancet 1995;345:761-2. 6. Gyulai R, Kemtmy L, Kiss M, et al. Herpes vires-like nucleic acid sequence in angiosarcoma in a patient without HIV infection. N Engl J Med 1996;334:540-1. 7. Weltfriend S, Friedman-Birnbaum R, Pollack S. Decreased natural killer cell function in patients with classical Kaposi's sarcoma. Dermatologica 1990;181:207-10. 8. Holden CA, Spittle MF, Wilson Jones E. Angiosarcoma of the face and scalp. Cancer 1987;59:1046. 9. Nanus DN, Kelsen D, Clark DGC. Radiation induced anglosarcoma. Cancer 1987;60:777-9. 10. Chadwick EG, Connor EJ, Hanson IC, et al. Tumours of smooth muscle origin in HIV infected children. JAMA 1990;263:3182-4. 11. McClain KI, Leach CT, Jenson HB, et al. Association of Epstein-Barr virus with N Engl J Med (1995);332:12-18. 12. Cesarman E, Chang Y, Moore PS, et al. Kaposi's sarcoma associated herpes vires-like DNA sequences in AIDS-related body cavity based lymphomas. N Engl J Med 1995;332:118691. 13. Gyulai R, Kemtmy L, Adam E, et al. HHV8 in angiolymphoid hyperplasia of the skin. Lancet 1996;347:1837.
Received for publication January 1996 Accepted following revision April 1997
Clinical Oncology
Case Report A Patient with Classical Kaposi's Sarcoma and Angiosarcoma: Bad Luck or a Common Aetiology? M. C. Steiner ~, M. E. F. Smith 2, M. F.Spittle 1 IThe Middlesex Hospital, 2UCL Medical School, London, UK
Abstract. Classical Kaposi's sarcoma and angiosarcoma are rare malignant turnouts arising from vascular tissue. However, they have distinct histological features and appear also to differ in their epidemiology and pathogenesis. We present the case history of a patient in whom both these turnouts occurred simultaneously. The relationship between these events is discussed in the light of the new viris, human herpes virus 8.
Keywords: Angiosarcoma; Human herpesvirus 8; Kaposi's Sarcoma
intermittendy required radiotherapy to the right foot and left hand. He did not develop significant limb lymphoedema. In April 1994 he presented again, with a lump behind the right knee, which had appeared 4 months previously. This region had not been irradiated previously. Clinical examination revealed a 4 cm red mass in the right popliteal fossa (Fig. 3). The lesion was biopsied and the histology showed a malignant vasoformative tumour with the features of angiosarcoma. The tumour comprised irregular anastomosing vessels lined by very plump and atypical endothelial cells (Fig. 4), with occasional tufting and a solid cell component, which was partly spindled and
CASE REPORT A 60-year-old, married man presented in 1983 with an 8year history of purple lesions on the feet. More recently, these had also appeared on the hands. He was of Catholic Sicilian origin, although he had lived in the UK for 30 years. His medical history included syncopal episodes and atrial fibrillation. At the time of presentation, his medications were phenytoin 300 mg at night and digoxin 0.125 mg daily. There was no family history of note. On examination, there were lesions typical of Kaposi's sarcoma (KS) on the feet and hands (Fig. 1). A biopsy specimen was taken from a lesion on his foot. The histology showed complex, irregularly shaped, dilated vascular channels in the dermis, lined by endothelial cells, some of which were atypical. The abnormal vessels were closely related to groups of plasma cells associated with abundant haemosiderin. No spindle cell component was seen. These features (Fig. 2) are diagnostic of Kaposi's sarcoma (patch phase). Immunological studies were performed, which demonstrated a defect in monocyte function. Precise details of these studies were unfortunately not available. The lymphocyte count and the helper/suppressor cell count ratio were normal. The patient's left foot was treated with a single fraction of 8 Gy midline dose radiation, using a cobalt-60 machine with lateral opposed fields. Six months later, the right foot required treatment and he received 15 Gy midline dose in five fractions with megavoltage photons. Over the next few years the condition remained indolent, although the patient
and offprint requests to. Dr M. Spittle, Department of Clinical Oncology, The Middlesex Hospital, Mortimer Street, London W1N 8AA, UK. Correspondence
Fig. 1. Typical lesions of Kaposi's sarcoma.
Fig. 2. Histological diagnostic features of Kaposi's sarcoma (patch phase).
187
A Patient with Classical Kaposi's Sarcoma and Angiosarcoma DISCUSSION
Fig. 3. Mass (4 cm) in the right popliteal fossa.
Fig. 4. Histological appearance of the mass shown in Fig. 3 showing the features of angiosarcoma.
partly epithelioid. Immunohistochemistry demonstrated that the turnout cells expressed CD3I, but lacked Factor VIII-related antigen. CD31 expression is highly specific for endothelial differentiation in the context of mesenchymal cells [1]. In view of this diagnosis and the site of disease, a wide local excision was performed followed by skin grafting. In April 1995, new lesions appeared on the dorsum and sole of the right foot, which were atypical of KS. These arose in areas of skin that had not been irradiated. The histology of a biopsy from the sole of the foot showed angiosarcoma, the appearances being similar to those of the previous biopsy from the popliteal fossa.
Classic (non HIV-related) KS is a rare tumour occurring in elderly males of Jewish or Mediterranean origin. Although it typically runs an indolent course, studies of the natural history of the disease have demonstrated an increase in the incidence of second malignancy in these patients, particularly involving the lymphoreticular system. Two such studies reported the rates of second malignancy to be 37% [2] and 15% [3] respectively. To our knowledge, the association of classic KS and angiosarcoma has not been reported. The geographical and racial distribution of classic KS suggests a genetic or environmental agent as a cause for the disease; this hypothesis has been supported by the discovery of herpesvirus-like DNA sequences from the virus termed human herpesvirus 8 (HHV8) in samples of tissue from patients with both AIDS-related and classic KS [4-6]. The occurrence of the disease in individuals with HIV infection, and in those receiving immunosuppressive therapy following organ transplantation, indicates that host defence factors are also crucial in the pathogenesis of this condition. Weltfriend et al. studied immune function in a group of patients with classic KS and found normal T4fr8 ratios, but significantly impaired natural killer cell function when compared with healthy controls [7]. It is likely that impaired immune function is not only a factor in the pathogenesis of classic KS but is also related to the high rate of lymphoproliferative malignancy found in these patients. Immunological studies in our patient showed an abnormality of monocyte function, the precise records of which were not available. We are therefore unable to ascertain whether this defect was implicated in the pathogeneis of this condition in this patient. Angiosarcoma is a clinically aggressive, malignant tumour showing endothelial differentiation. Holden et al. studied 72 patients who developed angiosarcoma on the head and neck (where it classically appears) and reported a 12% survival at 5 years [8]. This tumour has been widely reported in association with lymphoedema and prior irradiation [9]. Recently, HHV8 DNA sequences have been found both in angiolymphoid hyperplasia, eosinophilia and angiosarcoma [6]. Thus it is likely that the coexistence of these two malignancies in one patient can be attributed to the involvement of HHV8. The HHV8 status of this patient was not determined, but can be considered positive, as it is in almost all cases of KS. Although both KS and angiosarcoma show endothelial differentiation, their histological appearance are distinct [1]. The angiosarcoma in this patient appeared in a region that had not been previously irradiated, excluding this as an aetiological factor. Similarly, there was no lymphoedema at the site of the tumour. Since KS and angiosarcoma are both endothelial malignancies, it is perhaps surprising that angiosarcoma does not more often develop from preexisting KS lesions. This does not imply either distinct forms of endothelial differentiation in the two tumour types or little overlap in the genetic mutations that underlie their development. Although angiosarcoma does not appear to be associated with immunosuppression, Chadwick et al. have reported the occurrence of other soft tissue sarcomas (leiomysarcomas and leiomyomas) in children infected with HIV [10]. in addition, the Epstein-Barr virus (EBV) has been found in sarcomatous tissue taken from these children, but not in sarcomas from non-HIV controls [11]. The authors suggest that EBV infection in immunocompromised individuals may contribute to the pathogenesis of sarcomas. It is of interest that EBV has also been implicated in the pathogenesis of body cavity-based B-cell lymphomas in HIV-infected individuals, often in association with the
188 presence of KS-related herpesvirus [12]. These findings led support to the hypothesis that viral infection is an important factor in the development of tumours in the immunosuppressed. Such viruses are also likely to play a role in the pathogenesis of classic KS and may be involved in the development of multiple primary malignancies in these patients.
SUMMARY The circumstances underlying the occurrence of multiple primary malignancies in patients with classic KS has yet to be established. Both angiosarcoma and classic KS are derived from endothelial tissue, but the factors underlying their development appear to be distinct. Although it is likely that a combination of environmental and immunological factors resulted in the occurrence of these tumours in this patient, the relevant feature is the implication of HHV8 in both of these and other endothelial cell-derived malignancies [13]. This is the first reported occurrence of the coexistence of these two tumours.
References 1. Enzinger FM, Weiss SW. Malignant vascular tumours. In: Soft tissue tumours, third edition. St Louis, MO: C. V. Mosby, 641-77.
M.C. Steiner et al. 2. Safai B, Mike V, Giraldo G, et al. Association of Kaposi's sarcoma with second primary malignancies. Possible etiopathogenic implications. Cancer 1980;45:1472-9. 3. Friedman-Birnbaum R, Weltfriend S, Katz I. Kaposi's sarcoma: retrospective study of 67 cases with the classical form. Dermatologica 1990;180:13-17. 4. Huang YQ, Li JJ, Kaplan MH, et al. Herpes virus-like nucleic acid in various forms of Kaposi's sarcoma. Lancet 1995; 345:759-61. 5. Dupin N, Grandadam M, Calvez V, et al. Herpes virus-like DNA sequences in patients with Mediterranean Kaposi's sarcoma. Lancet 1995;345:761-2. 6. Gyulai R, Kemtmy L, Kiss M, et al. Herpes vires-like nucleic acid sequence in angiosarcoma in a patient without HIV infection. N Engl J Med 1996;334:540-1. 7. Weltfriend S, Friedman-Birnbaum R, Pollack S. Decreased natural killer cell function in patients with classical Kaposi's sarcoma. Dermatologica 1990;181:207-10. 8. Holden CA, Spittle MF, Wilson Jones E. Angiosarcoma of the face and scalp. Cancer 1987;59:1046. 9. Nanus DN, Kelsen D, Clark DGC. Radiation induced anglosarcoma. Cancer 1987;60:777-9. 10. Chadwick EG, Connor EJ, Hanson IC, et al. Tumours of smooth muscle origin in HIV infected children. JAMA 1990;263:3182-4. 11. McClain KI, Leach CT, Jenson HB, et al. Association of Epstein-Barr virus with N Engl J Med (1995);332:12-18. 12. Cesarman E, Chang Y, Moore PS, et al. Kaposi's sarcoma associated herpes vires-like DNA sequences in AIDS-related body cavity based lymphomas. N Engl J Med 1995;332:118691. 13. Gyulai R, Kemtmy L, Adam E, et al. HHV8 in angiolymphoid hyperplasia of the skin. Lancet 1996;347:1837.
Received for publication January 1996 Accepted following revision April 1997